The organic anion transporting polypeptides OATP1B1 and OATP1B3 are two major drug transporters expressed in human hepatocytes. Because of their multispecificity, these two transporters are potential sites of adverse drug-drug interactions. In the previous grant period, we characterized substrate dependent modulation, identified molecular characteristics of the substrate binding sites, and identified several amino acid residues important for OATP1B1- and OATP1B3-mediated substrate transport. However, the molecular mechanisms responsible for their multispecificities remain unclear. Our long term research goal is to understand in detail the mechanism of OATP-mediated transport as an essential prerequisite to understanding, predicting, and preventing OATP-related adverse drug-drug interactions. The rationale for the proposed research is that, because OATP1B1 and OATP1B3 are critically involved in the liver's ability to clear numerous chemicals from the blood, improved mechanistic insights into their individual and overlapping transporter functions will provide a strong scientific framework for improvements in the prediction and prevention of adverse drug-drug interactions, as well as the future design of specific substrates and/or inhibitors of their transport activity. The objective of this application is to identify domains and amino acids that are important for substrate translocation and stimulation, and to characterize the driving force(s) for transport. Our central hypothesis is that OATP1B1 and OATP1B3 transport their substrates via a central pore that includes substrate-specific translocation pathways, and that OATP1B1 and OATP1B3 work as asymmetrical exchangers. We plan to test the hypothesis with two specific aims: 1) Identify and characterize the translocation pathways of OATP1B1 and OATP1B3;and 2) Determine the mechanism of OATP-mediated transport. Completion of these specific aims will explain the substrate dependent effects by identifying amino acids in the different transmembrane domains that influence substrate translocation and will lead us a step closer to the three dimensional structure of these membrane transporters. Furthermore, we will resolve the controversies of the transport mechanism, identify a physiological counter-anion, and explain the allosteric effects that might be due to the oligomeric state of the transporters. This contribution is significant because its results will provide the fundamental understanding required to predict OATP- mediated drug transport, ultimately leading to more effective and efficient therapies in addition to fundamentally advancing the field of organic anion transport.
The proposed research is relevant to public health because a fundamental understanding of the structure/function relationships of OATP1B1 and OATP1B3 will provide the fundamental understanding required to predict OATP-mediated drug transport, ultimately leading to more effective and efficient therapies.
|Boxberger, Kelli H; Hagenbuch, Bruno; Lampe, Jed N (2018) Ligand-dependent modulation of hOCT1 transport reveals discrete ligand binding sites within the substrate translocation channel. Biochem Pharmacol 156:371-384|
|Li, Jibiao; Woolbright, Benjamin L; Zhao, Wen et al. (2018) Sortilin 1 Loss-of-Function Protects Against Cholestatic Liver Injury by Attenuating Hepatic Bile Acid Accumulation in Bile Duct Ligated Mice. Toxicol Sci 161:34-47|
|Zhao, Wen; Zitzow, Jeremiah D; Weaver, Yi et al. (2017) Organic Anion Transporting Polypeptides Contribute to the Disposition of Perfluoroalkyl Acids in Humans and Rats. Toxicol Sci 156:84-95|
|Kreznar, Julia H; Keller, Mark P; Traeger, Lindsay L et al. (2017) Host Genotype and Gut Microbiome Modulate Insulin Secretion and Diet-Induced Metabolic Phenotypes. Cell Rep 18:1739-1750|
|Zhang, Yuchen; Boxberger, Kelli H; Hagenbuch, Bruno (2017) Organic anion transporting polypeptide 1B3 can form homo- and hetero-oligomers. PLoS One 12:e0180257|
|Li, Yuan; McGreal, Steven; Zhao, Jean et al. (2016) A cell-based quantitative high-throughput image screening identified novel autophagy modulators. Pharmacol Res 110:35-49|
|Steiner, Konstanze; Zimmermann, Lisa; Hagenbuch, Bruno et al. (2016) Zebrafish Oatp-mediated transport of microcystin congeners. Arch Toxicol 90:1129-39|
|Stieger, Bruno; Hagenbuch, Bruno (2016) Recent advances in understanding hepatic drug transport. F1000Res 5:2465|
|Patik, Izabel; Kovacsics, Daniella; Német, Orsolya et al. (2015) Functional expression of the 11 human Organic Anion Transporting Polypeptides in insect cells reveals that sodium fluorescein is a general OATP substrate. Biochem Pharmacol 98:649-58|
|Tian, Jianan; Keller, Mark P; Oler, Angie T et al. (2015) Identification of the Bile Acid Transporter Slco1a6 as a Candidate Gene That Broadly Affects Gene Expression in Mouse Pancreatic Islets. Genetics 201:1253-62|
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